tbuckley/cabot-search huggingface dataset:
Abstract 5161: Molecular mechanisms of early-stage lung adenocarcinoma initiation
Authors: Alice Rodriguez-Fuguet, Luis Silva, John Asara, Xiaoman Li, Susumu Kobayashi, Wen Cai Zhang
Journal: Cancer Research (2023)

Abstract Lung cancer initiation and progression driven by epidermal growth factor receptor (EGFR) mutation has been extensively studied in the past decade. Though many leaps have been made in the field in terms of treatment, early diagnosis screening is not widely available or well established. Meanwhile, EGFR mutation is a significant driver of tumorigenesis and drug resistance. This receptor is related to many downstream pathways that influence cancer metabolism and the ability of tumor cells to adapt to changes in the tumor microenvironment. Our study finds that cancer metabolism plays a prominent role in the progression of tumorigenesis in early-stage lung cancer. Kynurenine, a metabolite from the tryptophan pathway, was highly upregulated in early-stage, EGFR-mutation driven lung cancer by metabolomic analysis. The connection between EGFR mutation and the upregulation of kynurenine remains largely unknown. We hypothesize that kynurenine, based on our preliminary data and as a ligand of the aryl hydrocarbon receptor, may have a dual role in early tumorigenesis. We propose that kynurenine may be used by tumor cells to modulate their response to stress by triggering anti-apoptotic pathways. Additionally, kynurenine may be used as a signaling molecule in the tumor microenvironment to allow the early tumor cells to evade immune detection through the transformation of macrophages from M1 to M2. Currently, our data show that indoleamine 2,3- dioxygenase 1 (IDO1), the rate-limiting enzyme of the tryptophan-kynurenine pathway, is significantly upregulated in early-stage, EGFR-driven lung cancer murine models by RNA-seq analysis. This supports our idea that IDO1 could help to modulate the response to cellular stress and to regulate the immune response to favor tumor development. We hope that IDO1 could be a potential clinical target and a potential biomarker for the dysregulation of this pathway. Citation Format: Alice Rodriguez-Fuguet, Luis Silva, John Asara, Xiaoman Li, Susumu Kobayashi, Wen Cai Zhang. Molecular mechanisms of early-stage lung adenocarcinoma initiation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5161.
Abstract 4149: Anti-CTLA-4 generates memory T-cells with greater expansion and functionality than anti-PD-1
Authors: Stephen Mok, Nana-Ama A.S. Anang, James J. Mancuso, James P. Allison
Journal: Cancer Research (2023)

Abstract Blocking either cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed cell death-1 (PD-1) pathway relieves the negative regulation of T-cells resulting in durable tumor rejection in patients with cancer and improved survival rate. However, it remains unclear how these immunotherapies affect memory T-cell response. Here we address whether anti-CTLA-4 and anti-PD-1 have different effects on memory T-cells. We used anti-CTLA-4 or anti-PD-1 therapy in combination with irradiated cancer vaccine in mice. After re-challenge, we observed that in murine tumor models, anti-CTLA-4 generates a more robust memory antitumor response than anti-PD-1 as demonstrated by smaller tumor volumes at all time points. We have traced and profiled antigen-specific CD8 T-cells throughout priming, memory phase, and re-challenge. We observed the memory responses generated by anti-CTLA-4 and anti-PD-1 diverge at priming; where anti-CTLA-4 generates more TCF-1+ memory-like T-cells than anti-PD-1, and remains apparent throughout activation and expansion as anti-PD-1 results in a higher percentage of TOX1+ terminally-differentiated T cells. During re-challenge, the memory T-cells generated by anti-CTLA-4 1) expand in greater frequency, 2) have greater cytokine production and antitumor activity, and 3) more frequently differentiate into the population of KLRG1+ effector CD8 T-cells than those generated with anti-PD-1. We found each of these traits correlated with a more effective memory response. Citation Format: Stephen Mok, Nana-Ama A.S. Anang, James J. Mancuso, James P. Allison. Anti-CTLA-4 generates memory T-cells with greater expansion and functionality than anti-PD-1. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4149.
Abstract 1750: Removal of mucin glycans by <i>Bifidobacterium bifidum</i> enhances chemotherapy-mediated cell death in mucinous adenocarcinomas
Authors: Leah K. Stripe, Amy C. Engevik, Mindy A. Engevik
Journal: Cancer Research (2023)

Abstract Background: Mucinous colorectal adenocarcinoma, a subtype of colorectal cancer, is characterized by mucin production and increased resistance to several chemotherapeutic interventions; resulting in a poorer prognosis compared to non-mucus secreting cancers. Advances in treatment are stymied by the limited number of efficacious chemotherapeutic agents. The most common drug used to treat colorectal cancer is 5-Fluorouracil (5-FU), but less than 10% of mucinous tumors respond to this drug. The production of mucus has been theorized to limit the uptake of chemotherapeutic agents via charge repulsion and size exclusion, thereby promoting chemo-resistance and driving poor outcomes. Hypothesis: We predict that mucin-degrading microbes secrete glycosyl hydrolase enzymes which cleave mucin glycans and promote the uptake of chemotherapeutic agents and enhance cell death. Methods &amp; Results: We queried the human gut microbiota and identified multiple diverse microbes which encode enzymes to degrade mucin glycans. Among the mucin-degrading bacteria, we found that Bifidobacterium bifidum harbored one of the most extensive repertoires of mucin-degrading enzymes. B. bifidum was grown in a chemically defined medium with or without porcine intestinal mucus and the secreted products were then added to mucus-producing adenocarcinoma cell lines: HT29-MTX and T84 cells. Supernatant from cultures with mucus removed sialic acid residues and enhanced 5-FU uptake after 48 hrs in both cell lines. Supernatant without mucus also promoted 5-FU mediated cell death; although to a lesser degree than supernatant from cultures incubated with mucus. Gene expression analysis and immunostaining revealed decreased MUC13 gene expression and protein in B. bifidum metabolite treated cell lines compared to media controls. In contrast, we found that secreted products from B. dentium, which is unable to degrade mucus, had no effect on 5-FU induced cell death. Conclusions: Our data suggests that B. bifidum elicits chemo-sensitivity via the production of mucin-degrading enzymes, which cleave negatively charged sialic acid, increasing the activity of 5-FU in these cancers as well as by lowering the expression of adherent mucins. This work points to a novel role of mucin-degrading microbes to promote 5-FU penetration of mucinous colorectal adenocarcinoma. This strategy has the potential to provide unique treatment strategies for patients with mucinous colorectal cancer. Citation Format: Leah K. Stripe, Amy C. Engevik, Mindy A. Engevik. Removal of mucin glycans by Bifidobacterium bifidum enhances chemotherapy-mediated cell death in mucinous adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1750.
Abstract 6004: DNA methylation diagnostics for upper urinary tract urothelial carcinoma using newly developed high-performance liquid chromatography
Authors: Mao Fujimoto, Eri Arai, Takuya Kikushima, Naotaka Nishiyama, Tomofumi Nakamura, Yuriko Yamada, Hiroaki Taira, Takuya Yotani, Hiroshi Kitamura, Yae Kanai
Journal: Cancer Research (2023)

Abstract Backgrounds: For diagnosis of upper urinary tract urothelial carcinoma (UTUC), conventional ureteroscopic examinations are invasive, and selective urine cytology has insufficient sensitivity. We have developed a new anion-exchange column for high-performance liquid chromatography (HPLC) with electrostatic and hydrophobic properties. Both cytosine and thymine, corresponding to methylated and unmethylated cytosine after bisulfite modification, respectively, are captured by electrostatic interaction and then discriminated from each other by their hydrophobic interactions. This method is expected to be very suitable for quantification of DNA methylation levels of cancer cells in urine samples with contamination of various cell lineages. Purpose: The aim of this study was to establish a less invasive and more accurate method for UTUC diagnosis based on DNA methylation quantification by our newly developed HPLC. Methods: Urine samples were collected by urinary catheterization during surgery for 218 urological cancer patients. Our previous studies have identified 4 CpG sites showing differences in DNA methylation levels between non-cancerous urothelium and UTUC based on genome-wide DNA methylation analysis using tissue specimens. In the present study, DNA methylation levels of these marker CpG sites were quantified by HPLC using the urine samples. Results: The thresholds have been set for the retention time by HPLC and the area under the chromatogram. Diagnostic criteria have been established to distinguish cases with current UTUC from non-urothelial cancer cases, bladder cancer cases and post-urothelial cancer treatment cases by combining marker CpG sites. The sensitivity and specificity were 90.9% and 87.0% respectively. Conclusions: Since HPLC-based DNA methylation diagnostic system was able to discriminate UTUC cells from blood cells and other contaminating cells in urine samples, application of our criteria will ultimately allow non-invasive diagnosis of UTUC in the clinical setting. It may be possible to at least partially replace highly invasive procedures such as ureteroscopy and to enable early initiation of treatment for UTUC resulting in improved prognosis. Citation Format: Mao Fujimoto, Eri Arai, Takuya Kikushima, Naotaka Nishiyama, Tomofumi Nakamura, Yuriko Yamada, Hiroaki Taira, Takuya Yotani, Hiroshi Kitamura, Yae Kanai. DNA methylation diagnostics for upper urinary tract urothelial carcinoma using newly developed high-performance liquid chromatography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6004.
Abstract 5056: ABN401 demonstrates robust anti-tumor efficacy in orthotopic PDX models of MET-driven NSCLC brain metastases in a pre-clinical study
Authors: Nirmal Rajasekaran, Kyung Eui Park, Saehyung Lee, Na Young Kim, Suk-Jae Chung, Young Kee Shin, Jun Young Choi
Journal: Cancer Research (2023)

Abstract Background Brain metastases (BM) are manifested in approximately 30-50% of patients with non-small cell lung cancer (NSCLC) and are associated with catastrophic implications on prognosis and survival. The development of blood-brain barrier-penetrant therapies for brain metastases of NSCLC is imperative and is a major clinical hurdle. ABN401, a highly potent and selective c-MET inhibitor, shows promising anti-tumor activity without significant safety concerns in patients with advanced NSCLC. Here, we report that ABN401 exhibits potent anti-tumor efficacy in pre-clinical orthotopic patient-derived xenografts (PDXs) derived from MET-driven NSCLC brain metastases. Methods Anti-tumor efficacy of ABN401 was assessed in two lung cancer PDXs (LU5349 and LU5406) from BM models harboring high-level MET amplification grown in NOD/SCID mice. Subcutaneous PDXs (n=14/group) were treated with ABN401 (60 mg/kg QD, 125 mg/kg QD, and 165 mg/kg QD) or control groups. Established PDXs were orthotopically implanted into the brain (n=14/group) and were treated with ABN401 (125mg/kg QD), or control groups. The tumor volume of orthotopic model was monitored using magnetic resonance imaging (MRI). Brain, plasma, and tumor samples were collected for pharmacokinetics (PK) and pharmacodynamics (PD) correlation analysis. Results The efficacy of ABN401(125 mg/kg QD) was confirmed in the subcutaneous PDX models (LU5349 and LU5406). Treatment with ABN401 showed up to 95% and 99% tumor growth inhibition in the LU5349 and LU5406 models, respectively. ABN401 (125 mg/kg QD) treatment induced complete or near-complete tumor growth regressions in the orthotopic tumor model. ABN401 also showed a desirable PK and safety profile with no significant changes in body weight. Conclusions ABN401 treatment showed robust anti-tumor efficacy in PDX models of MET-driven NSCLC brain metastases. Our findings suggest that ABN401 has excellent potential for treating NSCLC patients with BM and supports its ongoing clinical development. Citation Format: Nirmal Rajasekaran, Kyung Eui Park, Saehyung Lee, Na Young Kim, Suk-Jae Chung, Young Kee Shin, Jun Young Choi. ABN401 demonstrates robust anti-tumor efficacy in orthotopic PDX models of MET-driven NSCLC brain metastases in a pre-clinical study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5056.
Abstract 4734: BRD8-driven EP400 complex hijacks H2AZ to maintain proliferation in glioblastoma
Authors: Sherine Xueqin Sun, Olaf Klingbeil, Christopher Vakoc, Alea Mills
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM) is the most notorious primary brain tumor. The median survival of GBM patients is only about one year and about 95% patients succumb after five years. This gloomy picture has not been improved for decades, even with extensive treatments including surgery, radiotherapy, and chemotherapy. Hence, a better understanding of the mechanisms underlying GBM development may provide new therapeutic opportunities. Primary GBM generally harbors a low mutational load when compared to other human cancers. Even P53—the guardian of the genome that is essentially disabled in nearly all human cancers, remains unmutated in about 71% of GBM cases. Moreover, these P53 wildtype GBM cases are as aggressive as those with P53 mutations. To explore the mechanism by which P53 wildtype GBM thrive in the presence of intact P53, we performed CRISPR screens in a panel of human cancer cell lines using an sgRNA library specifically targeting the functional domains of ~200 chromatin regulators. We discovered that BRD8’s bromodomain—a druggable domain as shown by the tremendous success in preclinical and clinical trial in diverse cancers—is a vulnerability specifically in P53 wildtype GBM cases. Our mechanistic studies demonstrate that BRD8 functions through the EP400 chromatin remodeling complex and hijacks the histone variant H2AZ at P53 target loci, enforcing a compact chromatin state that blocks P53’s accessibility to its targets. We show that targeting the BRD8 bromodomain releases H2AZ, opens up chromatin, engages P53-mediated transactivation, and triggers growth arrest. Consistent with these findings, BRD8 is highly expressed with H2AZ in patient-derived proliferating GBM cells, and is inversely correlated with the expression of P53 targets. Our work solves a long-standing mystery in P53 wildtype GBM, and presents a promising therapeutic target for the majority of GBM patients. Citation Format: Sherine Xueqin Sun, Olaf Klingbeil, Christopher Vakoc, Alea Mills. BRD8-driven EP400 complex hijacks H2AZ to maintain proliferation in glioblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4734.
Abstract 4583: An essential role for Cmtr2 in endothelial cell function and vascular development
Authors: Alena Yermalovich, Zarin Mohsenin, Bruno Giotti, Douglas Wheeler, Kelly Xu, Alexander Tsankov, Matthew Meyerson
Journal: Cancer Research (2023)

Abstract Cancer genome sequencing studies have identified multiple novel tumor suppressor genes, including the FTSJD1 or CMTR2 gene that is subject to statistically significant levels of both nonsense and frameshift mutations in lung adenocarcinoma. However, these analyses are insufficient to determine the importance and modes of action of the gene in the disease. Follow-up functional studies are essential to elucidate these gene functions. The protein product of CMTR2 has been described as an mRNA cap methyltransferase, which O-methylates the ribose of the second guanine residue of the 5’ cap, likely serving to modify efficiency of transcript processing, translation and stability, but the details of how and why specific transcripts undergo methylation by the enzyme, as well as its role in oncogenesis, remain to be elucidated. In this study we report the first comprehensive analysis of the physiologic consequences of Cmtr2 deficiency in knockout (KO) mice and primary human cells. Constitutive deletion of Cmtr2 results in embryos that die in midgestation with defects in embryo size, placental malformation and yolk sac vascularization. Endothelial-specific deletion of Cmtr2 in mice also results in vascular defects and perinatal lethality, suggesting that vascular development is a key function of Cmtr2 in animals. In summary, our study reveals that Cmtr2 plays a critical role in vascular development, maturation and remodeling. Further studies of CMTR2 function may provide insight not only into lung cancer biology but also to its broader roles in ontogeny. Citation Format: Alena Yermalovich, Zarin Mohsenin, Bruno Giotti, Douglas Wheeler, Kelly Xu, Alexander Tsankov, Matthew Meyerson. An essential role for Cmtr2 in endothelial cell function and vascular development. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4583.
Abstract 6024: Precancerous nature of intestinal metaplasia with accelerated DNA methylation along with altered epigenomic landscape
Authors: Chihiro Takeuchi, Satoshi Yamashita, Yu-Yu Liu, Hideyuki Takeshima, Toshikazu Ushijima
Journal: Cancer Research (2023)

Abstract Objective. The presence of intestinal metaplasia (IM) is a risk factor for gastric cancer. However, it is still controversial whether IM itself is a precancerous or paracancerous lesion. Here, we aimed to explore the precancerous nature of IM in terms of epigenetic alterations. Design. Genome-wide DNA methylation analysis was conducted by EPIC BeadArray using IM and non-IM crypts isolated by Alcian blue staining. Organoid establishment, ChIP-seq for H3K27ac, and single-cell ATAC-seq were conducted using IM mucosa. NOS2 was induced using a Tet-on gene expression system in normal cells. Results. IM crypts had a methylation profile unique from that of non-IM crypts, showing extensive DNA hypermethylation in promoter regions with CpG islands, including those of tumor suppressor genes. Also, the IM-specific methylation profile was carried into a fraction of gastric cancers (GC), and the frequency of the IM-type GCs was higher than the fraction of IM cells in the adjacent mucosa, indicating that IM cells have a higher chance of developing into cancer cells than non-IM cells. Moreover, the patients with IM-type GCs showed better overall survival than those without, and IM-type GCs showed good response to chemotherapy. As for the mechanism of accelerated methylation induction, IM organoids had remarkably high endogenous NOS2 expression, and NOS2 induction in normal cells was shown to accelerate aberrant DNA methylation by increasing DNMT activity. IM mucosa underwent dynamic enhancer reprogramming, including the regions involved in abnormal NOS2 expression. Single-cell ATAC-seq also showed NOS2 open chromatin in IM cells but not in gastric cells, and frequent closed chromatin of tumor-suppressor genes in IM cells. NOS2 expression in IM-derived organoids was up-regulated by IL-17A, a cytokine secreted by extracellular bacterial infection. Conclusions. IM cells were considered to have a strong precancerous nature with an increased chance of converting into cancer cells in terms of the specific methylation profile and the accelerated DNA methylation induction due to abnormal NOS2 expression. Citation Format: Chihiro Takeuchi, Satoshi Yamashita, Yu-Yu Liu, Hideyuki Takeshima, Toshikazu Ushijima. Precancerous nature of intestinal metaplasia with accelerated DNA methylation along with altered epigenomic landscape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6024.